Natural Killer (NK) cells represent a promising frontier in cancer immunotherapy due to their inherent ability to recognize and kill tumor cells. This chapter explores the use of advanced in vitro models, such as organoids and organ-on-a-chip devices, to study the complex interplay between NK immune cells and human three-dimensional tumors. It provides a historical overview of the development of organoids and organ-on-a-chip technologies, emphasizing how these three-dimensional and dynamic models are becoming essential to faithfully replicate the human physiological environment in vitro. Although the fundamental concepts of organoids and organ-on-a-chip are different, they share the same goal of recapitulating complex human organs in vitro. Combining features from both concepts allows for a more powerful in vitro technology. Multicellular and multicompartmental systems are indeed extremely important for mimicking the three-dimensional tumor microenvironment conditions and dynamic immune cell recruitment and infiltration, improving the understanding of immune-tumor cellular behavior and interplay. Moreover, these innovative in vitro/ex vivo experimental approaches offer a promising alternative procedure for the prediction of tumor responses to immunotherapies during the preclinical testing, paving the way for more effective and targeted cancer therapies.